Many bioactive materials such as drugs have only limited solubility and/or stability in conventional liquid carriers and are therefore difficult to formulate and administer. In many cases, numerous administrations are required to achieve a desired therapeutic effect over an extended period of time. Various dosage forms and polymeric drug delivery devices and have been investigated for long term, therapeutic treatment of various diseases.
Certain polymers exhibit abrupt changes in aqueous solubility as a function of temperature. Certain of such polymers exhibit a lower critical solution temperature (LCST), wherein the interactive forces (e.g. hydrogen bonding) between water molecules and polymer molecules become unfavorable and phase separation occurs. Consequently, aqueous solutions of such polymers often display relatively low viscosity at ambient temperature and exhibit a sharp increase in viscosity following a small temperature increase, resulting in formation of a semi-solid gel. In certain polymers such a transition from a relatively low viscosity solution to a semi solid hydrogel occurs within in the range of mammalian body temperatures and therefore biodegradable embodiments of thermogelling (RTG) polymers have been investigated for use in a variety of biomedical applications such as drug delivery, tissue engineering, and wound healing. In such systems pharmaceutical agents are combined with an aqueous polymer solution at low temperature and, upon injection into a mammalian body, a hydrogel is formed such that the pharmaceutical agent can be released in a controlled manner. However, many of the RTG polymers examined to date have serious drawbacks when used in biomedical applications. Certain biodegradable polymers with reverse thermo gelling properties have been investigated in biomedical applications such as drug delivery, tissue engineering, and wound healing; wherein bioactive materials such as small molecule drugs, proteins or stem cells are mixed with the aqueous polymer solution at low temperature and subsequently form a semi-solid hydrogel upon introduction into a mammalian body.
Japanese Patent JP02078629 to Okada et al. (abstract) describes biodegradable block copolymers synthesized by transesterification of poly(lactic acid) (PLA) or poly(lactic acid)/glycolic acid (PLA/GA) and poly(ethylene glycol) (PEG). The resultant product was miscible with water and formed a hydrogel.
U.S. Pat. No. 5,702,717 to Cha et al. describes systems for parenteral delivery of a drug comprising an injectable biodegradable block copolymer-based drug delivery liquid having reverse thermal gelation properties. The systems thus described utilize a hydrophobic polymer block comprising a member selected from the group consisting of poly(α-hydroxy acids) and poly(ethylene carbonates) and a hydrophilic polymer block comprising polyethylene glycol (PEG). However, since most of the disclosed hydrogels have lower critical solution temperature (LCST) greater than 37° C. such compositions are unsuitable for most biomedical applications.
Martini et al. in J. Chem. Soc., 90(13): 1961-1966 (1994) describe low molecular weight ABA type triblock copolymers which utilize blocks of hydrophobic poly(ε-caprolactone) and blocks of hydrophilic polyethylene glycol. However, the in vitro degradation slow degradation rates for such copolymers greatly limits their use in sustained-release systems.
Thermosensitive water-soluble biodegradable polymers comprising polylactic acid (PLA) or polylactic acid/polyglycolic acid (PLA/PGA) blocks have been widely investigated for use in biomedical applications. However such compositions are known to generate lactic acid and glycolic acid upon biodegradation, wherein such acids may have adverse effects on acid sensitive drugs. Furthermore, such biodegradable polymers have limited stability when stored in aqueous solution.
Stratton et al., in WO 98/02142 describe compositions comprising polyoxyethylene-polyoxypropylene block copolymers (sold commercially under the trade name Pluronics®) having RTG properties for the delivery of proteins. However, such materials have limited use in biomedical applications since they are toxic to body organs and are nonbiodegradable. Moreover, only high molecular weight polyoxyethylene-polyoxypropylene block copolymers at higher concentrations (15-25 wt. %) exhibit RTG properties.
Other known thermosensitive polymers include poly(ethylene oxide)/polypeptide conjugates and pH-sensitive chitosan/glycerol phosphate compositions. While the degradation products of polypeptides are neutral amino acids and there is no significant pH drop during polymer degradation, such polymers are usually difficult to reproducibly synthesize; and chitosan/glycerol phosphate compositions are known to have low MW components, which may diffuse from the gel causing phase separation of pH sensitive chitosan molecules. In general, natural polymers are much less desirable than synthetic polymers because of batch-to-batch properties variation.
Still other known thermosensitive polymers include water-soluble polyphosphazenes. However, such polyphosphazenes have limited utility since they are not readily biodegradable. While such water-soluble poly(phosphazenes) have been studied for drug delivery applications, storage time in aqueous solutions is limited by slow hydrolysis.
Therefore there exists a need for injectable thermosensitive biodegradable hydrogels materials that may prepared by methods that allow for a high degree of control of all molecular, chemical and physical properties.
There exists another need for method for reproducibly providing carbohydrate, non-polysaccharide based materials with control of relative hydrophilicity/hydrophobicity.
There exists yet another need for thermogelling materials that may be conveniently modified or custom synthesized to accommodate the degradation rate, sol-gel transition temperature, critical gelation concentration, and permeability for specific applications requirements.
The present invention addresses these and other needs.